key: cord-0803297-f3uncobq
authors: Shah, Naveed Nazir; Nabi, Showkat Ul; Rather, Muzafar Ahmad; Kalwar, Qudratullah; Ali, Sofi Imtiyaz; Sheikh, Wajid Mohammad; Ganai, Alveena; Bashir, Showkeen Muzamil
title: An update on emerging therapeutics to combat COVID‐19
date: 2021-06-11
journal: Basic Clin Pharmacol Toxicol
DOI: 10.1111/bcpt.13600
sha: facdffd7a2edfc4c97f7434aac16f01ad600388c
doc_id: 803297
cord_uid: f3uncobq

BACKGROUND: The COVID‐19 pandemic has demanded effective therapeutic protocol from researchers and clinicians across the world. Currently, a large amount of primary data have been generated from several preclinical studies. At least 300 clinical trials are underway for drug repurposing against COVID‐19; the clinician needs objective evidence‐based medication to treat COVID‐19. OBSERVATIONS: Single‐stranded RNA viral genome of SARS‐CoV‐2 encodes structural proteins (spike protein), non‐structural enzymatic proteins (RNA‐dependent RNA polymerase, helicase, papain‐like protease, 3‐chymotrypsin‐like protease) and other accessory proteins. These four enzymatic proteins on spike protein are rate‐limiting steps in viral replications and, therefore, an attractive target for drug development against SARS‐CoV‐2. In silico and in vitro studies have identified various potential epitomes as candidate sequences for vaccine development. These studies have also revealed potential targets for drug development and drug repurposing against COVID‐19. Clinical trials utilizing antiviral drugs and other drugs have given inconclusive results regarding their clinical efficacy and side effects. The need for angiotensin‐converting enzyme (ACE‐2) inhibitors/angiotensin receptor blockers and corticosteroids has been recommended. Western countries have adopted telemedicine as an alternative to prevent transmission of infection in the population. Currently, no proven, evidence‐based therapeutic regimen exists for COVID‐19. CONCLUSION: The COVID‐19 pandemic has put tremendous pressure on researchers to evaluate and approve drugs effective against the disease. Well‐controlled randomized trials should assess medicines that are not marketed with substantial evidence of safety and efficacy and more emphasis on time tested approaches for drug evaluation.

The global epidemic of novel coronavirus (nCoV) began in Wuhan, China, reporting the first case on 31 December 2019. [1] [2] [3] [4] [5] Within four months, the disease was reported from more than 180 countries affecting 36 million and causing the death of 3.6 million humans globally. 2, 6 Owing to the disease characteristics of global presence and transmission rate, WHO declared the infection as a pandemic. 6, 7 Subsequently, WHO named the new coronavirus entity "2019-nCoV," which stands for "2019 novel coronavirus" and disease caused by it as COVID- 19 , an acronym that stands for coronavirus disease-2019. This novel Betacoronavirus has been proposed to have animal origin from Wuhan's seafood market, 8 resulting in human infection of animal origin. 9 The phylogenetic analysis virus is proposed to have originated from bats through an unknown mammalian host to humans. 3 Furthermore, phylogenetic analysis indicates nCoV is related to SARS-CoV-1, 5,10,11 which led the International Virus Classification Commission (ICTV) to name it "SARS-CoV-2". 5, 9 Clinically, the disease spectrum ranges from mild respiratory tract illness (self-limiting), severe pneumonia, organ failure and death. 7

The virus belongs to the genus betacoronavirus 12 and has been reported from mammals, birds, and humans. 13 Based on serological cross-reactivity and phylogenetic analysis, betacoronavirus is divided into three subgroups. Group I and Group II are responsible for causing disease in domestic animals, and group III for avian species. Studies in China have identified Group I and group II coronavirus from the upper respiratory tract of humans suffering from "atypical pneumonia". [14] [15] [16] Structurally, coronavirus is a group of positive sense-single stranded enveloped RNA viruses composed of the spike (S), envelope (E), membrane (M) and nucleocapsid (N) protein. 17, 18 Coronaviruses show variable severity in their hosts and have been found to infect respiratory, enteric, hepatic and nervous systems. 19 Most infections caused by coronavirus are relatively mild but newly emerged strains of nCoV have shown a high degree of pathogenicity and change in cell tropism. 20 The high affinity/avidity of COVID-19 to ACE-2 receptor compared with SARS Cov-1 and other coronaviruses causes great threat to humans. 21 Preclinical and clinical studies have postulated acute respiratory distress syndrome (ADRs) as the cause of death in COVID-19. 22 ADRs' common mechanism in SARS-CoV-2, SARS-CoV, and MERS-CoV infection involves a deadly uncontrolled cytokine storm. 23 Cytokine storm involves the uncontrolled release of pro-inflammatory cytokines and chemokines from immune cells of COVID-19 patients, resulting in an unwanted inflammatory response and, subsequently, extensive tissue damage. 24 Furthermore, clinical evaluations have proposed pro-inflammatory cytokines and chemokines that cause the proliferation of specific cells and inhibit specific cells and release of acute-phase proteins. 3 Thus, the pathogenesis of COVID-19 leads to the cytokine release syndrome (CRS), which is an acute systemic inflammatory response characterized by multiple organ dysfunction.

Throughout human civilization, influenza epidemics occur periodically, and some of them are converted into pandemics. 25 The Spanish flu of 1918-1919, considered the mother of all plagues, affected one third of the global population and caused almost 50 million deaths worldwide. 26 The Spanish flu occurred in three distinct waves; the first wave began in spring 1918 from a Kansas military farm and spread to the entire America and Europe. 27 The second wave occurred spontaneously in august 1918 from several locations widely separated, and the scientists warned that this deadlier plague can wipe out more than half of the world population. By 1919, the third wave of an epidemic caused heavy mortality in America and Europe. 28 The most sticking feature of Spanish flu was the "W" pattern of the mortality curve, which means a disease caused higher mortality in young people, the geriatric population, as well as the middle age group. 29 Researchers found that the key to flattening the Spanish flu curve in 1919 was herd immunity, social distancing and quarantine of infected and suspected individuals. 30 1956-1957 witnessed the advent of Asian flu as a potential epidemic when influenza A (H2N2) subtype was isolated from patients showing ARDS. 31 The 1956 epidemic resulted in 60,000 deaths in the USA, followed by the emergence of the influenza A (H3N2) subtype in 1968-1969 named the Hong Kong flu, which passed almost unnoticed due to spontaneous waxing in the autumn of 1969. 32 An alarming observation of the Hong Kong flu was the co-circulation of H1N1 subtype and H3N1 subtype, which led the scientific community to speculate about mixing two subtypes and henceforth emergence of novel influenza virus. 33 Fortunately, an epidemic was contained in 7 months from the date of its earliest occurrence using cutting-edge biological methods and other prophylactic measures. 34 The 21st century witnessed the second influenza epidemic of influenza A (H1N1) in May 2009, which affected northern hemisphere countries in two waves. 35 This epidemic of 2009 showed higher mortality in the age group of 5-20 years, while the least mortality was observed in the senior age group due to some residual immunity (>50 years). CDC attributed more than 30% of deaths in the 2009 epidemic to secondary bacterial infection. 36 Earlier, pandemics/epidemics were controlled by travel restrictions, proper quarantine measures 37 and supportive treatment to clinically ill patients.

An extensive literature survey was conducted through electronic search such as science direct, PubMed, Scopus, Web of science, J Gate and Google scholar. 46 Search terms used were COVID-19, SARS-CoV-2, 2019 and coronavirus. The names COVID-19, SARS-CoV-2 and coronavirus were combined with In silico, In vitro, clinical trial, treatment and vaccine. Search terms COVID-19, SARS-CoV-2 and coronavirus 46 resulted in more than 300 clinical trials to find evidence-based medicine against COVID-19 on 5 May 2020. Table 1 provides detailed clinical trial information in different stages, including clinical trials (completed, active, recruiting and not yet recruiting) and the number of patients in the experimental and placebo group. The literature cited in a present review dated from 1918 to 2020 and was limited to English. Furthermore, the study contains data obtained from clinical trials in different phases of evaluation. The final data collected were then compiled, evaluated, compared and conclusions drawn accordingly.

Presently, there are no effective approved therapeutics (specific antiviral agents) or prophylactics (vaccines) available against COVID-19, which could treat clinically ill patients and reduce virus shedding and hence inhibit transmission of disease. 6 Globally, there are reports which suggest a number of drugs that could serve as potential candidates against COVID-19, but the clinical efficacy of these drugs remains yet to be evaluated. Owing to the non-availability of effective medicines for COVID-19, currently, researchers are working on a three-pronged strategy to develop effective drugs against COVID-19; these include (a) in-silico/in-vitro studies, (b) drug repurposing and (c) denovo drug discovery against COVID-19. Remdesivir, a potent viral polymerase inhibitor, can be effective against COVID-19. A recently completed clinical trial has offered encouraging result of using remdesivir in COVID-19 patients, which led the FDA to grant emergency use authorization to remdesvir. 47 Contrary to this, lopinavir and ritonavir, an antiviral drug combination used against HIV, have completely failed to offer a significant advantage in COVID-19 patients. 47 In the present review, an attempt has been made to summarize major therapeutic and prophylactic interventions against COVID-19 with their clinical outcomes and shortcomings.

A SARS-CoV-2 virus is akin to SARS-CoV, and MERS-CoV and spike (S) protein of SARS-CoV-2 virus consist of an S1 and S2 subunit; cellular interaction involves the binding of the S1 subunit of the virus with ACE-2 receptor of the host cell. 48 This interaction and subsequent endosome formation for cellular internalization are facilitated by host type 2 transmembrane serine protease, TMPRSS2 ( Figure 1 ). 49 On cellular translocation, viral RNA is translated on host cellular machinery to synthesize viral polypeptides. The synthesis of viral RNA follows this by RNA-dependent RNA polymerase enzyme [49like3-chymotrypsin-like protease (3CL pro )] enzyme that plays a crucial role in processing the viral RNA. Further, followed by the packaging of viral RNA and viral structural proteins to form viral particles released from the cell exocytosis against COVID-19 patients. The mechanism of action of this drug combination in COVID-19 remains yet to be identified, but it has been confirmed that main viral proteases of SARS-CoV-2 are not inhibited by this drug combination. Recently, a study has identified boceprevir, calpain/cathepsin inhibitors as potent chemotypes that inhibits the enzymatic activity of SARS-CoV-2, hence inhibit assembly of viral particles ( Figure 2 ). 47,50,51

The in-silico strategy uses molecular databases and bioinformatics tools to screen molecules/drugs for their effectiveness. It offers the advantage of high-throughput screening, elucidation of new functions of drug molecules. 52 In silico strategies provide requisite preliminary information on the efficacy of compounds for further validation in in vitro and in vivo studies. Coronavirus binds via S protein with ACE-2 receptor located on host cell followed by receptor (TMPRSS2) mediated endocytosis for cellular invasion. 53,54 Based on molecular databases 55 analysed all possible proteins of SARS-CoV-2 identified 2 human targets ACE2 and TMPRSS2 enzymes. Both are potential targets to inhibit entry of the virus into cells. 56 They constructed surface glycoprotein sequence of SARS-CoV 2 and found spike glycoproteins dock with human ACE-2 receptor to further support these propositions. Spike proteins of SARS-CoV-2 have 10-20 times more affinity for ACE-2 receptor than SARS-CoV, which may be one of the possible reasons for the increased infectivity of SARS-CoV-2. 57 Furthermore, in silico studies found AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (CGK) enhance binding of viral S protein with host ACE-2 receptor and attributed increased susceptibility of lung tissue to the presence of AAK1 and CGK on lung alveolar epithelial cells. 58 Consequently, 59 found that baricitinib effectively blocks AAK1 and CGK and suggested clinical evaluation of baricitinib against SARS-CoV-2. The docking score of the N-terminal receptor binding domain of S protein revealed methyl Tanshinonate as a potential candidate for blocking S protein binding with ACE-2. 60,61 A battery of neutralizing monoclonal antibodies (mAbs) was constructed via protein database against MERS-CoV spike (S) protein of the virus, and a majority of these antibodies (mAbs) was found to bind to the N-terminal domain (NTD) of the S1 subunit of MERS-CoV. 62 Duan et al 63 constructed a phage-display library from B cells of SARS CoV convalescent patients for designing and neutralizing antibodies targeting epitope of spike protein on the S2 subunit.

Analysis of viral proteinase of SARS-CoV-2 using bioinformatics tools (ZINC drug database) identified papainlike protease (PL pro ), RNA-dependent RNA polymerase (RdRp) and 3-chymotrypsin-like protease as rate-limiting steps in the life cycle of SARS-CoV-2 and proposed drug designing against these enzymes. 64 An earlier study has determined the three-dimensional MERS-CoV papain-like protease (PLpro) by X-ray crystallography and found that it comprises two domains, an ubiquitin-and a catalytic domain. They proposed that pharmaceutical entities having the potential to cause mutagenesis of the deficient oxyanion hole of PLpro will cause unfolding of PLpro, hence subsequent loss of enzymatic activity PLpro can help drug designing against SARS-CoV-2. 56, 58 In silico, evaluation of eucalyptol indicated absolute binding of eucalyptol to COVID-19 PL pro . 65 Molecular analysis studies of SARS-CoV, MERS-CoV and SARS-CoV-2 found RNA-dependent RNA polymerase (RdRp) highly conserved, suggesting clinical evaluation of RdRp inhibitors for the treatment of SARS-CoV-2. 66 

A novel approach of vaccine development using computational techniques, including immunogenomics, immunogenetics and bioinformatics, is called vaccinomics. 67 In 2004, study utilized bioinformatics and structural analysis to design proteins corresponding to the S1 surface regions of SARS-CoV and immunized them in rabbit and monkey. Antiserum collected was found to elicit specific antibodies to SARS-CoV, which strongly supports synthetic-peptide-based approaches for generating a vaccine against coronavirus. 67 sequence alignment (MSA) found RdRp protein highly conserved in all human coronavirus strains and identified sequence WDYPKCDRA as highly immunogenic and accessible to the host immune system. Therefore, the study concluded that the target sequence could develop a universal vaccine against human coronavirus. 68 Novel nucleoside analogue designed by flex-base modification of the fleximers was combined with acyclic sugar moiety of acyclovir was found to inhibit replication of several human coronavirus strains. 69 Furthermore, Epitope Database and Analysis Resource of SARS-CoV, MERS-CoV, and other coronaviruses were used to identify candidate immune targets against SARS-CoV-2. This led to the identification of an array of regions in SARS-CoV-2, which have a high degree of homology with SARS-CoV and MERS-CoV and hence can serve as possible candidates for vaccine development against COVID-19. 70 

Driven by predictive information, in vitro studies offer an advantage to gear discovery of drug candidates. Molecular studies on virus-cellular receptor interaction found TMPRSS2 as cellular host factor critical for the spread of clinically relevant viruses, including coronaviruses and influenza A viruses. 71 An in vitro study by Ref. 72 evaluated postulates of in-silico studies in a human cell line (293T) and found the entry of the virus into the host cell is facilitated by S1 subunit of spike (S) protein which binds with angiotensin-converting enzyme 2 (ACE2). This is further supported by findings showing that serum from a COVID-19-recovered subject inhibits virus entry into cells of a human alveolar cell line and on Calu-3 cell line(pulmonary and intestinal). Moreover, camostat mesylate, a clinically approved serine protease inhibitor of TMPRSS2, partially inhibits SARS-CoV-2 entry into Caco2 and VeroE6/TMPRSS2-expressing cells, 2 reinforcing the applicability of cell culture models for drug discovery. 73, 74 Patients who recovered from COVID-19 have a high concentration of neutralizing antibodies against viral S1 protein. 75 Based on these results, a study using serum from convalescent patients in cell line sera was found to significantly reduce SARS-2-Spike driven entry in host cell. 76 Based on these study results, it may be proposed that antibody response against S1 subunit may partially protect during infection.

Earlier in vitro studies have reported antiviral activity of ivermectin against dengue virus, 77 human immunodeficiency virus 77 and simian SV40 virus. 78, 79 Ivermectin (antiparasitic drug) exhibited antiviral activity on Vero-hSLAM cell line infected with SARS-CoV-2. It resulted in a 5000-fold reduction in viral RNA after 48 hours in the Ivermectin group compared with the control group. 80 Remdesivir, a C-adenosine nucleoside triphosphate analogue, has shown activity against various RNA viruses (Coronavirus, Ebola virus and Flavivirus) by entering viral RNA chain and inhibiting RNA synthesis ( Figure 3) . Presently, in vitro and laboratory animal studies using remdesivir have shown promising results against SARS-COV-2. 81 These studies reported the effectiveness of F I G U R E 1 Inhibition of viral spike protein binding with cellular receptors. Bromhexine hydrochloride and arbidol hydrochloride inhibit docking of ACE-2 with S1 subunit hence inhibits viral phagocytosis (cellular internalization). Camostat inhibits TMPRSS2 cellular receptor, which is needed for priming of S protein and facilitation of docking between S1 and ACE-2 remdesivir in viral replication, reduction in viral load and early resumption of symptoms in experimentally infected rats. 82 In vitro studies have found chloroquine effective against HIV, 83 influenza, 84 H5N1 virus, 85 Chikungunya virus, 86 Zika virus, 87 Crimean-Congo haemorrhagic fever virus 88 and herpes simplex virus. 89 Studies using chloroquine on epithelial lung cell cultures were found to inhibit SARS-CoV replication. 90 Studies on the Vero cell line found that chloroquine causes deficit glycosylation in S protein receptors of viruses required for binding with angiotensin-converting enzyme 2 (ACE2). 91 In vitro studies using Vero E6 cell line have proposed chloroquine as an effective drug in reducing viral replication at a dosage achievable in lungs. 92 Chinese researchers who studied chloroquine's effect on SARS-CoV-2infected cell line found the drug highly effective in reducing viral replication at a dosage achievable in the lung due to its effective penetration in lung tissues. [93] [94] [95] [96] Furthermore, studies found that hydroxychloroquine (HCQ) more effectively inhibits SARS-CoV-2 replication than chloroquine. 97 The mechanism proposed for antiviral activity involves inhibition of essential steps in the viral life cycle, including glycosylation of cellular receptor, reductase-2 cathepsins MAP-kinase that inhibits viral assembly of SARS-CoV-2 and retard viral infection. 7,98,99 HCQ, when used in combination with other drugs, has been found to have potent activity against COVID-19. 96 An in vitro study has recently found synergistic action of combinational therapy of remdesivir (antiviral drug) and chloroquine against SARS-CoV-2. 99 In vitro studies have suggested antiviral activity of HIV protease inhibitors (lopinavir/ritonavir) against SARS-CoV-2. 100 However, their efficacy is questionable against SARS-CoV-2 as coronavirus proteases do not contain a C2-symmetric pocket, which targets HIV protease inhibitors. 82, 101 An in vitro study found ribavirin effective against SARS-CoV-2 at higher concentrations than required to inhibit other types of viruses. 99 A recent study on mouse models found more substantial evidence for anti-MERS-CoV activity of antiviral remdesivir than HIV protease inhibitors (Lopinavir/Ritonavir). 82 The main protease M pro of SARS-CoV-2 is involved in cleavage of viral polypeptides, and an earlier study has successfully treated feline infectious peritonitis using GC376,

a dipeptide-based protease inhibitor. 107 They found inhibitory action of GC376 against SARS-CoV-2 in cell culture. Hence, they proposed use of GC376 in clinical trials for development of a therapeutic regimen against COVID-19. To identify potent inhibitors of SARS-CoV-2 main protease, Ma et al 47 conducted a study using enzyme kinetic studies; mass spectrometry, thermal shift binding and fluorescence resonance energy transfer enzymatic assay and found that boceprevir and calpain inhibitors II and XII have a significant inhibitory activity against SARS-CoV-2 main protease. Furthermore, they found that these compounds inhibit SARS-CoV-2 replication in cell culture. They proposed use of these compounds in clinical trials for development of an effective therapeutic regimen against SARS-CoV-2. While, majority of the M pro inhibitors of SARS-CoV-2 have γ lactam glutamine surrogate at the P1 position, and caplian inhibitor II and XII have hydrophobic moiety at P1 position. X-ray crystallographic studies have found that this hydrophobic moiety occupies the S1 pocket in an inverted binding pose, and hence, they can provide a new direction for development of an effective therapeutic regimen against SARS-CoV-2. 108 Papain-like proteases PLpro of SARS-CoV-2 are essential for posttranslational modifications of viral polypeptides and generation of functional replicase complex hence play important role in viral transmission. 109 Recently, a study found that inhibition of SCoV2-PLpro with GRL-0617 reduces viral replication. 110 Based on these findings, it is an urgent need to understand molecular rules governing PLpro substrate specificity, which can be helpful in designing effective drugs for COVID-19. 111 

Drugs used earlier against SARS-Cov and MERS are eligible candidates to develop a therapeutic regimen against COVID-19. Clinically investigated repurposed drugs that have shown promise in clinical trials against COVID-19 are summarized in Table 2 . These drugs offer advantages as medicines have proven harmless, pharmacokinetics is well understood, and optimal dosages are standardized. 92 Recently after an outbreak of COVID-19, Ref. 129 has summarized almost 31 broad-spectrum antiviral agents (BSAA) as potential candidates for drug re-profiling against COVID-19. Clinical trials identified at Clinicaltrials.gov related to drug F I G U R E 3 Inhibition of RNA-dependent RNA polymerase and viral assembly. Remdesivir inhibits RNA-dependent RNA polymerase hence inhibits viral RNA synthesis, while HCQ/ Chloroquine causes alkalization of endosomes hence inhibits viral particle assembly repositioning for COVID-19 treatment are summarized and discussed below.

A pilot clinical study (open-label, randomized and controlled) was conducted to evaluate the efficacy of Recombinant human angiotensin-converting enzyme 2 (rhACE2) against COVID-19. The study could not yield any encouraging result and was withdrawn after 7 days. 46 Recently, Tian et al 130 found that SARS-CoV-specific human monoclonal antibody CR3022 binds with receptor-binding domain (RBD) of COVID-19 and blocks the viral receptor (ACE-2) of cells and inhibit cellular infection. 130 Epitope of CR3022 and ACE2 binding site in COVID-19 RBD did not overlap. Therefore, the other potent specific neutralizing antibodies, such as m396 and CR3014, targeting the ACE2 binding site of SARS-CoV could not bind to COVID-19 S protein. Thus, CR3022 is a potential therapeutic choice for COVID-19 infection, alone or combined with other neutralizing antibodies. A study conducted on cell culture and laboratory animals found that the pan-coronavirus fusion inhibitor, EK1 peptide, was effective in reducing viral load. Both the EK1 and peptide HR2 domain could effectively block the transmission of the COVID-19 virus. 131 Furthermore, a lipopeptide EK1C4 generated from EK1 was found to be a more potent fusion inhibitor against S1 subunit of spike protein of SARS-CoV-2 compared with EK1. 131 

A clinical trial against the Middle East respiratory syndrome (MERS) used lopinavir (HIV type 1 aspartate protease inhibitor) in combination with ritonavir (inhibitor of cytochrome P450). The synergistic action of combinational drug preparation was attributed to increased bioavailability of lopinavir in the presence of ritonavir. 83 An open-label, randomized clinical trial was conducted in Wuhan, China, to evaluate the efficacy of lopinavir-ritonavir in clinical cases. 116 Patients (n = 199) with confirmed COVID-19 infection were stratified as per the severity of disease as vindicated by ventilator support. Patients were divided into two groups; one group received standard care (n = 100) and the other group (n = 99) was treated with standard therapy in addition to lopinavirritonavir (400 mg and 100 mg, respectively) twice a day for 14 days. Unfortunately, results were not encouraging as no improvement was observed in clinical improvement, viral load (detectable viral RNA) at different intervals. Although based on intention-to-treat analysis, the median time for recovery in the lopinavir-ritonavir group was one day lesser than the control group. On day 13, lopinavir-ritonavir treatment was stopped because of adverse gastrointestinal, renal and immunosuppressive events. Ineffectiveness of drugs may be attributed to a heterogeneous patient population, 131 lower concentration achieved in serum compared with levels needed to inhibit replication of virus. 3 Little is known about the tissue concentration of drug achievable at tissues where SARS-CoV-2 is replicating. 77 

Chloroquine emerged 70 years ago as a substitute for natural quinine and is currently the drug of choice against malaria in most countries. 7, 132, 133 Hydroxychloroquine is derived by hydroxylation of the side chain of chloroquine. Chloroquine has been found effective in autoimmune diseases, 134 inflammatory processes, human immunodeficiency virus (HIV) 7 bacterial, fungal and viral infections. 135 A clinical trial conducted in Chinese patients found that chloroquine has a profound effect on clinical outcome and decreasing viral load in COVID-19 patients. 136 Recently, chloroquine repurposing was evaluated in 100 patients in China. A clinical study reported encouraging results, including an early decline in viral fevers, resolution of lung pathology (computed tomography images), and earlier clinical recovery compared to the control group in COVID-19 treatment. 136 Studies have reported that chloroquine causes glycosylation of the glycoprotein (gp120) envelope of the human immunodeficiency virus and renders viral particles non-infectious. 10, 11 Furthermore, chloroquine has been found to inhibit Quinone Reductase 2, 11 involved in the biosynthesis of sialic acid, 137 an important component of ligand recognition, 7 and it causes alkalization of endosomes-hence inhibiting ph-dependent endosomemediated viral entry. 138 Chloroquine enhances cell-mediated immune response directed against the viral antigen by increasing export of soluble antigen from dendritic cell to human cytotoxic CD8 + T cell. 7, 11 Recently, contradictory results were published in the New England Journal of Medicine. 139 The study was conducted in a Chinese patient with confirmed COVID-19 infection. The patient was treated with hydroxychloroquine, standard treatment and with standard therapy. After two weeks, the patients received hydroxychloroquine showed deterioration in respiratory symptoms and showed need of respiratory escalation support, while no improvement was reported in clinical presentation, viral load and haematological profile.

Remdesivir, a broad-spectrum antiviral pro-drug that undergoes metabolism to C-adenosine nucleoside triphosphate analogue and causes premature termination of RNA transcription, has shown potent activity against COVID-19 in an in vitro study. 4 Earlier studies reported inhibitory action of remdesivir on viral replication of related virus of the betacoronavirus group at doses well tolerated. 140 Reduced mortality was observed in Ebola virus-infected patients treated with remdesivir (33%) (n = 499) compared to patients (75%) (n = 1900) treated with standard therapy. 141 Currently, Remdesivir is being evaluated in a phase-I, controlled trial (randomized, double-blind, placebo-controlled) with a loading dosage of 200 mg and 100 mg maintenance dosage daily and has not presented any toxic effects. 142 Successful results have been reported in patients showing mild to moderate COVID-19. 143 6 | COMBINATIONAL

Currently, a clinical trial has found increased efficacy of a combinational therapeutic regimen using widely available drugs, for which large-scale manufacture is possible and those drugs that can be prescribed immediately. 144 Combinational therapy of non-specific antiviral drugs (lopinavir, ritonavir and favipiravir) used earlier in influenza and HIV are currently under investigation for phase IV clinical trials against COVID-19. 145 Clinical improvement in early viral clearance and improvement in clinical signs has been reported by combinational therapy of antiviral drugs (lopinavirritonavir, ribavirin) and interferon-α against Middle East respiratory syndrome coronavirus (MERS-CoV). 146 Umifenovir (membrane fusion inhibitor) used with remdesivir (RdRp inhibitor) was found to be effective against Ebola virus, 147 SARS-CoV and MERS-CoV. The same combinational therapy is presently under investigation against SARS-CoV-2. 148 Gautret et al 149 conducted a clinical trial (open-label, non-randomized) using hydroxychloroquine and azithromycin for treatment of COVID-19. The results of their study proposed that hydroxychloroquine used in combination with azithromycin causes a significant reduction in viral load and amelioration of symptoms in COVID-19 patients. Their study recommended the possibility of the adoption of this combinational therapeutic protocol to fight the merging viral epidemic in real time. Based on these results, Chinese experts recommended 500 mg chloroquine two times for ten days in patients affected with COVID-19 pneumonia. 150 

COVID-19 patients are primarily presenting with respiratory symptoms, 134 gastrointestinal symptoms 151 and myalgia/arthralgia. 152 A Chinese medicine system is based mainly on symptomatic treatment, 153 and Chinese medicine (CM) has classified the COVID-19 as dampness type of sickness. 56, 99, 154 As per the Chinese system of medicine, the pathogenesis of infectious diseases has a relation with the weather. 155 The pathogenesis of COVID-19 was proposed due to endogenous stagnated heat due to warm temperatures in November and an abrupt decrease in temperature during the latter part of November, which resulted in exogenous cold-dampness. 156 A phylogenetic analysis and timeline match of the outbreak 157 support these propositions. Accordingly, as per Chinese medicine, treatment of COVID-19 should focus on eliminating dampness and releasing endogenous stagnated heat, which will result in removing lungs, henceforth expelling pathogenic factors. 158, 159 An In silico study has proposed a plausible Chinese medicine mechanism, and the authors suggested that Chinese medicinal preparations (kaempferol and baicalin in da-yuan decoction) bind to ACE-II receptors and can inhibit cellular infection by COVID-19. 160 Similarly, a molecular docking study of 24 Chinese medicine preparations recommended a cocktail of seven herbal medicines that can bind with the S-protein of ACE2. 161 Chinese medicinal preparations regulate key immunogenic pathways and pro-inflammatory signalling pathways, which could help alleviate pneumonia in COVID-19 patients. [162] [163] [164] Chinese patients have reported potential benefits of Chinese medicine in terms of pyrexia, radiological changes, hospital stay and viral load reduction. 93, 109 These findings support the use of Chinese medicine with proper standardization and caution as an adjuvant for the management of COVID-19.

Studies investigating the viral pathogenesis of pneumonia have attributed cytokine storm as a possible pathogenesis pathway involved in viral pneumonia and have found a beneficial role of corticosteroids in H1N1 pneumonia, SARS-CoV, (MERS)-CoV and other types of pneumonia. 153, 163, 164, 165 This is further supported by in vitro studies in A549 lung epithelial cells where dexamethasone was found to block cytokineinduced apoptosis. 3 So, beneficial effects of corticosteroids have been attributed to suppression of unwanted immunopathological response-hence cytokine storm in viral pneumonia, 3, 166 However, contradictory findings were reported with the use of corticosteroids in COVID-19 patients as these drugs modulate inflammation and immune activation that delays viral clearance. 167 Furthermore, the use of corticosteroids in COVID-19 has reported of adverse effects, which include osteoporosis, diabetes and psychosis with its use. 167 A meta-analysis has reported increased mortality, secondary bacterial infection and fungal infection in influenza patients receiving corticosteroids. 168 Despite these limitations, there are few clinical trials underway in different parts of the world to use corticosteroids against COVID-19. Because of insufficient clinical evidence, WHO does not support the clinical use of corticosteroids in COVID-19 patients. 169 In spite of this, encouraging results have been reported in Spain using corticosteroids against SARS-CoV-2. Clinical investigators reported significant reduction in all-cause mortality without any complications. In addition, almost 10 randomized, controlled trials have reported significant reduction in mortality, need of high-pressure ventilation and hospital stay in patients treated with corticosteroids. 170 In patients with severe manifestation of COVID-19, hyperinflammatory response has been reported which results in pulmonary thrombosis henceforth acute lung injury and extravasations of cellular debris, which eventually causes multiple organ failure. 171 So, a plethora of studies have proposed a beneficial role of corticosteroid in COVID-19 to mitigation of hyper-inflammation and acute respiratory distress syndrome. 170, 172, 173, 174 There is ample evidence to support elevation of cytokine profile in COVID-19, which is an indication of secondary haemophagocytic lymphohistiocytosis, which is effectively responsive to use of corticosteroids. 175 In addition, corticosteroids cause down-regulation of inflammatory pathways, which is a prerequisite to restore tissue homeostasis and cause resolution of pulmonary and extra-pulmonary organ damage. 176 Hence, the beneficial role of corticosteroids may be attributed to pathophysiological reasoning.

The rationale of using immunomodulatory agents in COVID-19 is to spare host tissue from unwanted inflammatory response induced by cytokine storm. Early studies in China found that IL-6 (Interleukin-6) is a key proinflammatory cytokine, which plays a role in multiple organ failure in COVID-19 patients. 83 Subsequently, a clinical trial was designed in 21 patients treated with Tocilizumab (400 mg), a monoclonal antibody IL-6 receptor antagonist. 21 Results were encouraging as 91% of patients showed clinical recovery and enhanced blood oxygen levels, amelioration of pulmonary tissue damage and reduced hospitalization time. 21 This trail's limitations were fewer patients recruited, absence of placebo comparator and a heterogeneous patient group. 48 Pirfenidone, an inhibitor of IL-1β and IL-4, and Sarilumab, another IL-6 receptor antagonist, are being evaluated for beneficial effects against COVID-19 patients. 177, 178 Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth, has revealed successful pulmonary oedema resolution in COVID-19 patients. Fingolimod, a sphingosine-1-phosphate receptor regulator, has been successfully used against multiple sclerosis; a clinical trial 128, 179 using Fingolimod and ventilator support has reported resolution of inflammation and histopathological change in pulmonary tissue of COVID-19 patients.

Immunoglobulins have found applicability in a diverse set of diseases ranging from acute idiopathic thrombocytopenic purpura to chronic inflammatory demyelinating polyneuropathy. 180 The main advantage of using immunoglobulins in those diseases which are refractory to conventional therapeutic options is that immunoglobulins recognize a broad set of glycoproteins and protein shell in enveloped and un-enveloped virus, respectively. 181, 182 There is no commercial preparation of immunoglobulin to offer protection against COVID-19, so the only option left is convalescent plasma obtained from recovered patients. There are reports of successful use of plasma therapy in SARS-CoV-1 and MERS patients. 183 Currently, immunoglobulins are being clinically evaluated in uncontrolled case series comprising 5 patients and other series of 3 patients in China. 184 Reports suggest immunoglobulin efficacy with 7-10 days of infection when the primary immune response is insufficiently developed. 185 Subsequently, the FDA has issued a guideline to study the use of immunoglobulins obtained from patients recovered from COVID-19. Some authors have questioned the use of immunoglobulin in SARS-CoV-2 owing to its high rate mutation to change surface glycoprotein to evade the immune system. 182 

Telemedicine involves the use of information technology for providing expert advice from a distance. 186 Face-to-face contact plays an essential role in patient and doctor relationship. 187 However, overcrowded patient wards create more infection and contamination in an environment that renders the health of medical staff and patients at higher risk. 128 To avoid transmission of infection to the healthy population, telemedicine offers an alternative for providing health care without physical contact between patient and physician with the added advantage of low cost and extensive coverage. 188 Presently, western countries 189 are focusing and investing in telemedicine to contain the spread of COVID-19 infection. 190 The Brazilian government has launched the "Coronavírus SUS" app to track and identify COVID-19-infected patients on similar lines; the United Kingdom has developed a mobile application that enables patients to self-report their health conditions. 191 Furthermore, the American Psychological Society, 2020 and WHO, 2020 has proposed the use of telemedicine in alleviating the adverse psychological effects associated with loneliness, lockdown and quarantine.

Due to the non-availability of evidence-based pharmaceutical preparation against COVID-19, the disease is currently managed by symptomatic care in combination with full intensive care support. This section will discuss adjunctive therapies under clinical investigation. Vitamin C, evaluated in COVID-19 patients because of its antioxidant activity, immune-modulator action and anti-inflammatory action, 123 has reported improvement in clinical conditions and sepsis, and reduced mortality. 192 Thalidomide causes increased degradation of mRNA of tumour necrosis factor-α (TNFα), which explains its anti-inflammatory action. 193 In addition to this, thalidomide causes release of interleukins and activation of natural killer cells. Therefore, being evaluated as supportive therapy in addition to conventional therapy. 194 An important issue related to thalidomide use the development of Amelia in new born babies from mothers who are underwent with thalidomide treatment during pregnancy. 194 Recombinant human interferon α2β is reported to have an inhibitory effect on MERS-CoV and SARS-CoV 195 and has been proposed for evaluation against COVID-19. Synergistic action of pegylated interferon alfa-2a and alfa-2b in combination with ribavirin is under investigation 196 with a rationale to activate an innate immune response against SARS-CoV-2. Researchers have cautioned against using interferons due to side effects associated with their use and recommended close monitoring of patients undergoing interferon therapy. 197 Griffithsin, a gel obtained from red algae, contains lectins that specially bind with surface glycoprotein (gp-120) of HIV and spike (S) proteins of SARS-CoV-1, and it inhibits penetration of the virus into the cell. 198 Given its encouraging results in SARS-CoV-1 and HIV, chemical constituents should be evaluated in SARS-CoV-2.

Coronaviruses have a propensity to spread in a broad host range, and they periodically jump into new host species and emerge as an epidemic for immunologically naïve humans; the current outbreak of COVID-19 is the 3rd outbreak in the 21st century after SARS-CoV and MERS-CoV. Therefore, broad-spectrum antiviral therapy is an unmet medical demand at present to control the epidemic of CoVs infection. In silico and in vitro are rapid time-saving and cost-saving strategies that can guide research in a situation like COVID-19 with a higher likelihood of finding desired results with the added advantage of screening drugs for toxic action. The development of novel drugs/vaccines against COVID-19 will take months to years. However, scientist needs to focus on repurposing of drugs with special emphasis on drugs used against other human coronaviruses SARAS-CoV and MERS. Utmost caution should be taken as the published reports are mostly from countries affected early in the pandemic; therefore, results from these studies should be cautiously extrapolated.

During a pandemic like the COVID-19, there is a need to emphasise time-tested approaches for drug evaluation in randomized, controlled clinical trials. Drugs yet to be marketed should be evaluated by well-controlled randomized trials with substantial evidence of safety and efficacy. It is unclear whether combinational therapy provides an added synergistic advantage over monotherapy in terms of a favourable risk/benefit ratio because of the lack of monotherapy primary data. Since COVID-19 has an immense number of treatment interventions, we did not cover all available therapeutic approaches. Moreover, the findings of the studies are complex and modify as new evidence arises. Besides, only English articles/publications were reviewed, so some important international data could be lacking.

Although there are conserved druggable SARS-CoV-2 targets, including S protein, RdRp, helicase, PLpro and 3-CL protease, unfortunately, no drug or vaccine is currently available against the coronavirus. The pandemics have raised serious concerns and have put pressure on researchers throughout the world for evaluating and approving drugs against COVID-19. There is limited evidence of the effectiveness and adequacy of studies of drugs currently used in the treatment of COVID-19. The FDA has currently approved drugs against COVID-19 on little evidence, lesser clinical trials/drugs and suboptimal design of the clinical trial, which may not give the actual picture of the efficacy of these drugs. Recently, USA issued an Emergency Use Authorization (EUA) to use hydroxychloroquine, and there is no conclusive evidence of its efficacy. Although currently undergoing clinical trials based on repurposing of drugs have not yielded enough encouraging results, there are some takeaways from these trials. The speed, efficacy and priority with which the studies were designed to provide early answers can be extrapolated for other drugs and other epidemic situations.

Furthermore, these studies give convincing evidence regarding potential adverse effects of active pharmaceutical preparations used in a clinical trials. With the ongoing effort, we hope that COVID-19 will subside in the coming months. Still, there is an urgent need to develop a universal vaccine or broad-spectrum antiviral against human coronavirus.

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The authors fully acknowledge the officials of the Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, for their support.

SHAH et Al.

The authors declare no conflicts of interest.

Naveed Nazir Shah, Showkat Ul Nabi, Showkeen Muzamil Bashir and Muzafar Ahmad Rather contributed significantly to the conception and design of the study. Sofi Imtiyaz Ali, Qudratullah Kalwar, Wajid Mohammad Sheikh and Alveena Ganai assisted in writing the manuscript and revised the manuscript decisively for imperative intellectual content. All authors read and approved the final manuscript.

https://orcid. org/0000-0002-0983-5157